WO2013048956A2 - Procédé de séparation par extraction en phase solide - Google Patents

Procédé de séparation par extraction en phase solide Download PDF

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Publication number
WO2013048956A2
WO2013048956A2 PCT/US2012/056874 US2012056874W WO2013048956A2 WO 2013048956 A2 WO2013048956 A2 WO 2013048956A2 US 2012056874 W US2012056874 W US 2012056874W WO 2013048956 A2 WO2013048956 A2 WO 2013048956A2
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WO
WIPO (PCT)
Prior art keywords
column
spe cartridge
solvent
water
ahl
Prior art date
Application number
PCT/US2012/056874
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English (en)
Other versions
WO2013048956A3 (fr
Inventor
Roger Pettitt
Willy SKJOLD
Mette FALCK-PEDERSEN
Original Assignee
Ge Healthcare Limited
Medi-Physics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ge Healthcare Limited, Medi-Physics, Inc. filed Critical Ge Healthcare Limited
Publication of WO2013048956A2 publication Critical patent/WO2013048956A2/fr
Publication of WO2013048956A3 publication Critical patent/WO2013048956A3/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B01D15/08—Selective adsorption, e.g. chromatography
    • B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
    • B01D15/32—Bonded phase chromatography
    • B01D15/325—Reversed phase
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

Definitions

  • the present invention relates to a method for separating a precursor to a diagnostic imaging agent useful for positron emission tomography (PET) imaging.
  • PET positron emission tomography
  • the present invention is directed to a method of separating a precursor to [ 18 F]fluciclatide.
  • [ 10 F]-Fluciclatide is a diagnostic PET agent for the imaging, among other things, malignant diseases, heart diseases, endometriosis, inflammation-related diseases,
  • [ F]-Fluciclatide is also useful in anti- angiogenic imaging and therapy follw-up against, e.g. , high-grade glioma, renal cell carcinoma, melanoma, invasive breast tumours, distant metastases, head, and neck tumors.
  • the end synthesis of the agent can be performed at PET centers using automated synthesis platforms inculding the TRACERlab FX F-N platform or the FASTlab platform, both from GE Healthcare Ltd, Amersham, U.K.
  • the precursor of [ 18 F]-fluciclatide, AH111695 is typically after synthesis purified using high-pressure liquid chromatography (HPLC) equipment.
  • HPLC high-pressure liquid chromatography
  • HPLC to purify the precursor [ F]-fluciclatide is that the purified product is isolated in a solution containing mostly water, which takes almost four weeks to remove. There is therefore a need in the art for alternative method for separating/isolating the precursor [ F]-fluciclatide
  • the invention relates to a method for purifying AH111695 from one or more aquous AH111695-containing solutions by passing the AH111695- containing solutions through an SPE cartridge or column, thereby trapping the AH111695 in the SPE cartridge or column; and washing the SPE cartridge or column with a second solvent thereby releasing the AH111695.
  • the invention in another aspect, relates to amethod for removing water from one or more aquous AH111695-containing solutions by passing the AH111695-containing solutions through an SPE cartridge or column, thereby trapping the AH111695 in the SPE cartridge or column; and washing the SPE cartridge or columnwith a second solvent thereby releasing the AH111695.
  • FIG. 1 depicts an example of reverse phase SPE cartridge or column for use in the method of the present invention.
  • [ F]FBA 4-[ FJfluorobenzaldehyde
  • AH111360 4-trimethyl ammonium benzaldehyde
  • AH111360 4-trimethyl ammonium benzaldehyde
  • the crude [ 18 F]FBA is typically purified on a SPE (solid phase extraction) cartridge to remove excess 4-trimethyl ammonium benzaldehyde, reaction by-products, Kryptofix 222, and other impurities.
  • the [ 18 F]FBA is eluted from the cartridge with an organic solvent and is subsequently reacted with the peptidic precursor AH111695 in the presence of an aqueous buffer solution, thereby yielding [ 18 FJfluciclatide.
  • the peptidic precursor to [18F]-fluciclatide, AH111695 is manufactured via a multi-step synthesis culminating in preparative HPLC purification in a resource- intensive, lengthy, and expensive process.
  • Multiple preparative-HPLC (“prep-HPLC”) runs are required per batch. Each run not only yields numerous fractions containing AH111695, but each fraction also contains a relatively large volume of water. Each batch, for example, contains 75% water, with the balance being an organic solvent, such as acetonitrile.
  • Each fraction is freeze-dried and later combined by re-dissolution in water and freeze-dried again. The overall time used for these two freeze-drying cycles is 3.5 weeks.
  • Embodiments of the present invention seek to obviate the need for removing the copious amounts of water that result from the multiple prep-HPLC runs used to purify AH111695 that is produced in large scale (10-40 grams per batch), though the embodiments can also be applied to small scale production ( ⁇ 5 mg) of AH111695.
  • the invention relates to a method for separating AH111695 from one or more aquous AH111695-containing solutions (e.g., where the AH111695 has been pre-purified using prep-HPLC) by passing those solutions through an SPE cartridge or column.
  • the AH111695 is captured in an SPE cartidge as the one or more aquous AH111695-containing solutions are passed through the SPE cartidge or column.
  • all of the one or more aquous AH111695-containing solutions e.g., prep- HPLC fractions
  • the one or more aquous AH111695-containing solutions contain mostly water, e.g., up to 75% water, up to 80%, up to 85% water, up to 90% water, up to 95% water or up to 100% water.
  • the balance of the aqueous AH111695- containing solutions is made up of an organic solvent, such as acetonitrile.
  • the AH111695-containing solutions will also contain an organic acid, such as trifluoroacetic acid (e.g., 0.1%).
  • the SPE cartridge or column used to capture the AH111695 contains a stationary phase (e.g., silica gel or a polymer polystyrene divinylbenzene resin with reverse-phase chromatography properties.) that has been modified.
  • the stationary phase is modified to contain a hydrocarbon chain having a length longer than C-8, preferably longer than C-18; most preferably, a C-30 hydrocarbon chain.
  • FIG. 1 depicts an example of reverse phase SPE cartridge or column for use in the method of the present invention.
  • the cartridge 100 is filled with a stationary phase 102.
  • the cartridge 100 includes an elongate tubular body 104 defining a cylindrical cavity 106.
  • a first end 108 of body 104 includes a transverse annular wall 110 defining an exit aperture 112 in fluid communication with cavity 106.
  • Annular wall 110 also supports an elongate open tubular wall 114 forming a luer tip 116.
  • the opposing second end 118 of body 104 supports an end cap 118 having a cap body 120 defining an inlet aperture 122 in fluid communication with cavity 106.
  • Cap body 120 includes an outer annular rim 122 engaging the outer surface 124 of tubular body 104 at second end 118 and an inner annular wall 126 engaging the inner surface 128 of tubular body 104 at second end 118.
  • Cartridge 100 also includes circular disc-shaped porous filter elements 130 and 132 spanning across cavity 106 with stationary phase 102 between.
  • cartridge 100 is, in some embodiments, about 5 to about 20 cm in length (e.g., about 5 to about 25 cm; about 10 to about 25 cm; about 5 to about 15 cm in length; about 10 to about 15 cm in length; about 5 to about 10 cm in length; or about 8 to about 15 cm in length) and the cavity 106 about 5 to about 15 cm in diameter (e.g., about 5 to about 10 cm in diameter; or about 10 to about 15 cm in diameter), although the size and shape of cartridge 100 may be selected as will be suitable for its intended purpose.
  • the SPE cartridge or column should have the capacity for purifying the aqueous AH111695-containing solutions from four prep-HPLC runs (e.g., ⁇ 7 to 40 grams of AH111695).
  • the term "diameter” refers to inner diameter.
  • Suitable assembled SPE cartridge or column s for use in the present invention can are commercially available from, e.g., Macherey-Nagel GmbH & Co. Diiren, Germany; Biotage AB, Uppsala Sweden; or Grace Davison Discovery Sciences, Deerfield, IL (MODcol® Spring® loaded columns).
  • Suitable stationary phases for use in an SPE cartridge or column can be any stationary phase known in the art including, but not limited to those, commercially available from Princeton Chromatography Inc., Cranbury, NJ. In some embodiments, the stationary phase allows low back pressure. Several factors contribute to back pressure, e.g. particle size (e.g., 40-80 ⁇ ; pore size 60-120 A; and/or surface area of 250-400 m2/g).
  • a suitable stationary phase is a C-30 stationary phase.
  • a C-30 cartridge is preferred as it provides higher retention capability or binding capacity compared to shorter-chain reverse phase cartridges (e.g., C-8 or C-18) and can be used for the separation of AH111695 from water and free TEA.
  • the one or more aquous AH111695-containing solutions are diluted with water prior to passing them through the SPE cartridge or column .
  • the amount of water is effectively increased by removing any organic solvent (e.g., acetonitrile) contained in the aquous AH111695-containing solutions.
  • the amount of water should be sufficient to ensure that any organic solvent present in the one or more aquous AH111695-containing solutions is sufficiently low so as to ensure capture of the AH111695 in the SPE cartridge or column.
  • the AH111695-containing solutions are diluted with water, or the organic solvent is removed, to the extent that the solutions contain up to 85% water, e.g., up to 90% water, up to 95% water or up to 99%+ water.
  • the diluted HPLC fraction (or the HPLC fraction from which a part or substantially all of the organic solvent has been removed) is passed through the cartridge (e.g., using of a pump, by positive pressure using an inert gas, such as nitrogen, or by gravity) and the AH111695 is substantially quantitatively retained by the stationary phase inside the SPE cartridge or column.
  • the SPE cartridge or column in which the AH111695 is captured can be washed with an aqueous solvent, particularly in instances where there is free TEA present, e.g., from the prep-HPLC process.
  • UV-Vis spectrophotometry can be used for such monitoring, either in-line (i.e., as the solvent exits the SPE cartridge or column) or batch- wise (e.g., aliquots collected as the solvent exits the SPE cartridge or column or aliquots taken from the bulk solvent collected). All of the aqueous solvent (e.g., 100% water) used to wash the SPE cartridge or column, while the AH111695 is captured therein, is collected in a suitable receptacle.
  • aqueous solvent e.g., 100% water
  • the amount of aqueous solvent used to wash the SPE cartridge or column in some embodiments, is about 500 mL, e.g., from about 100 mL to about 2000 mL; from about 100 mL to about 2000 mL; from about 500 mL to about 1000 mL; from about 100 mL to about 1000 mL; or from about 100 mL to about 500 mL.
  • the aqueous solvent used to wash the SPE cartridge or column in some embodiments, is 100% water, but may contain up to 10 % of an organic solvent, e.g., from about 2% to about 10%; about 2% to about 5%; or about 5% to about 10%.
  • the amount of organic solvent present in the aqueous solvent should be sufficiently low so that AH111695 does not elute from the SPE cartridge or column.
  • the SPE cartridge or column can be washed using a solvent gradient that can be changed manually, or in an automated fashion, to vary as a function of time. For example, the SPE cartridge or column can be washed with 100% water for a certain period of time. The percentage of water can then be decreased over time and supplemented with a equal percentage amount of a second, non-aqueous solvent (e.g., if the amount of water is decreased to 80%, the amount of second solvent would be 20%).
  • the cartridge can be washed with 100% of the second solvent.
  • the change to the second solvent can occur gradually, over time, it can be changed in a single step.
  • the SPE cartrige can be washed with 100% water for a given amount of time and, at a certain point, the solvent can be changed to 100% of the second solvent immediately.
  • the second solvent is an organic solvent.
  • organic solvents include acetonitrile, hydoxilic solvents or mixtures thereof.
  • exemplary hydroxylic solvents include, without limitation, methanol, ethanol, propanol (e.g., n- butanol and iso-propanol), and butanol (e.g., n-butanol, iso-butanol, sec-butanol, and t- butanol), or mixtures thereof.
  • the solvent can be changed to a percent amount of second solvent sufficient to elute (i.e., release) the AHl 11695 from the SPE cartridge or column. In some instances, 20% or greater (e.g., 25% or greater; 30% or greater; 50% or greater; 70% or greater; 90% or greater; or 100%) of the second solvent, the balance being water, is sufficient to elute the AHl 11695 captured in the SPE cartridge or column. It should be kept in mind, however, that one of the objectives of the embodiments of the present invention is to remove water from the one or more aquous AH111695-containing solutions. Accordingly, in some embodiments, there is a preference to maintain the amount of water used along with the second solvent to a minimum.
  • the aquous AH111695-containing solutions can be introduced/loaded onto the SPE cartridge or column.
  • the SPE cartridge or column is then washed with an aqueous solvent that may contain an amount of organic solvent sufficiently low so that AHl 11695 does not elute from the SPE cartridge or column.
  • the SPE cartridge or column can then be allowed to run dry and the stationary phase can be dried substantially by flowing an inert gas (e.g., nitrogen) through it.
  • the second solvent which may contain some water, can be introduced onto the SPE cartridge or column so as to elute the AH111695.
  • the second solvent does not contain any water.
  • elution of the AH111695 from the SPE cartridge or column can be monitored by methods known in the art.
  • UV-Vis spectrophotometry can be used for such monitoring.
  • the AH111695-containing eluent is collected in a suitable receptacle.
  • the collected AH111695-containing eluent can be further processed, e.g., by removal of the solvent, which in some instances can contain water, via evaporation of the solvent using a roto-evaporator, by distillation, by freeze- drying or a combination of these techniques.
  • the residue that remains after the removal of the solvent is isolated AH111695.
  • the purity of the AH111695 can be evaluated by methods known in the art, including, 1H NMR, UV-Vis, and/or IR.
  • the isolated AH111695 may require further processing to remove, e.g., trifluoroacetic acid (TFA) that may be left over from the prep-HPLC pre-purification.
  • TFA trifluoroacetic acid
  • Removal of contaminants like TFA can be effected by adding water to the residue and removing the water by freeze-drying.
  • the TFA may be effectively removed by adding water containing 5-15% acetonitrile, then removing the water- acetonitrile in vacuo.
  • the claimed method helps reduce the time necessary to isolate AH111695 that has been pre-purified by preparatory HPLC from almost four weeks, in one instance, to 1-2 days.
  • AH111695 was synthesized according to a procedure similar to the one described in WO2006/030291, which is incorporated by reference as if fully set forth herein. Briefly, 38 g (0.02 mol)the compound of the formula (AH111570):
  • AH111695 (60 mg) was dissolved in 20 mL CH3CN/H20 + 0.1% TFA (22/78). This solution was further diluted with 40 mL 0.1% TFA in water to make a stock solution with concentration of AH111695 of about 1 mg/mL.
  • the column e.g., Sepra- C-18-E; Isolute C-4; Varian BondElut C-2; or Strata 8B-S100-HCH
  • a 5 mL aliquot of the stock solution was applied on the column over 3-4 minutes. In some instances, 5 x 1 mL aliquots are applied to the column.
  • the column was dried under vacuum after the sample was applied, though in some embodiments, the column can be washed with water after the product is applied. Ethanol was then applied to the column and the column was soaked for 2 minutes before the elution started. The elution was performed two times with 5 mL ethanol. The eluent was analyzed using HP- 1100 series HPLC- DAD. The water content of the product-containing solution was reduced from 90+% to about 10%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Treatment Of Liquids With Adsorbents In General (AREA)
  • Extraction Or Liquid Replacement (AREA)

Abstract

La présente invention concerne un procédé de séparation/isolement du AH111695 présent dans une ou plusieurs solutions aqueuses contenant du AH111695, cela comprenant ses sels libres, ledit procédé consistant à faire passer lesdites solutions contenant du AH111695 à travers une cartouche ou une colonne d'extraction en phase solide, de façon à piéger le AH111695 à l'intérieur de la cartouche ou de la colonne d'extraction en phase solide ; et à laver ladite cartouche ou colonne d'extraction en phase solide avec un second solvant afin de libérer le AH111695.
PCT/US2012/056874 2011-09-30 2012-09-24 Procédé de séparation par extraction en phase solide WO2013048956A2 (fr)

Applications Claiming Priority (2)

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US201161541647P 2011-09-30 2011-09-30
US61/541,647 2011-09-30

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WO2013048956A2 true WO2013048956A2 (fr) 2013-04-04
WO2013048956A3 WO2013048956A3 (fr) 2013-08-15

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006030291A2 (fr) * 2004-09-14 2006-03-23 Ge Healthcare As Composes pour diagnostics
WO2008072976A2 (fr) * 2006-12-13 2008-06-19 Ge Healthcare As Synthèse d'un peptide radiofluoré utilisant la technologie d'activation par micro-ondes
WO2011044422A2 (fr) * 2009-10-08 2011-04-14 Ge Healthcare Limited Procédé de purification par extraction en phase solide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006030291A2 (fr) * 2004-09-14 2006-03-23 Ge Healthcare As Composes pour diagnostics
WO2008072976A2 (fr) * 2006-12-13 2008-06-19 Ge Healthcare As Synthèse d'un peptide radiofluoré utilisant la technologie d'activation par micro-ondes
WO2011044422A2 (fr) * 2009-10-08 2011-04-14 Ge Healthcare Limited Procédé de purification par extraction en phase solide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Preparative Chromatography Introduction", , 1 January 2003 (2003-01-01), XP0055044648, Retrieved from the Internet: URL:http://www.discoverysciences.com/uploadedFiles/Preparative_and_Process/PrepProcessPurif_ProdInfo_PrepackedCols_p148to151_p156to161.pdf [retrieved on 2012-11-19] *

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